Pyrexia in a patient with megaloblastic anemia: a case report and literature review.

Deficiency of vitamin B12 and/or folic acid as a cause of pyrexia, though known, is rarely reported in literature. We aimed to report a case in a 51 year old woman, who presented with fever and pancytopenia and was diagnosed to have megaloblastic anemia secondary to vitamin B12 and folate deficiency. The pyrexia subsided following the intramuscular injection of vitamin B12 and oral folic acid administration. All the other infective, inflammatory/autoimmune, endocrine causes of pyrexia were excluded by appropriate investigations. Therefore, we suggest that all physicians be aware of megaloblastic anemia as a treatable cause of pyrexia in order to avoid unnecessary costly investigations and antibiotic usage.

which she had regular cycles. There was no history of cough with expectoration, headache, arthralgia, and rash, and nor was there a history of recent travel to malaria endemic zone or exposure to any patient of tuberculosis.
Examination of the patient revealed pulse rate of 118 per minute, blood pressure of 110/70 mm Hg (supine), and oral temperature of 38.3°C (101°F). She had moderate conjunctival pallor and scleral icterus. There was no lymphadenopathy, clubbing, eschar, or skin rashes. Oxygen saturation was 99% on room air, and there were no signs of respiratory distress in the patient. Cardiovascular examination revealed a systolic flow murmur in the aortic area. The respiratory and nervous system examinations were within normal limits. Her chest X-ray and abdomen ultrasound revealed no significant abnormalities except for mild hepatomegaly.

Clinical Progression
Pending laboratory investigation reports, and in view of neutropenia, the patient was started prophylactically on broad spectrum intravenous antibiotics (on day 2) based on the protocol of infection management for a period of 4 days but the patient continued to be pyrexial. Therefore, in view of the positive laboratory investigations pointing towards megaloblastic anemia along with the absence of any positive microbiological findings, the patient was started on injection vitamin B 12 and oral folic acid (on day 5) along with on-going parenteral antibiotics. Pyrexia settled on day 6 of admission with just vitamin B 12 and folic acid therapy and, consequently, the antibiotics were withdrawn (figure 3).
Given the patient's low hemoglobin, she was transfused with 3 units of packed cell volume. The patient improved symptomatically after being prescribed vitamin B 12 and folic acid supplements,  following which the patient was discharged in a stable condition. Routine follow-up (at one month) showed normalization of vitamin B 12 (656 pg/mL) and folate (>5 ng/mL) levels as well as improvement in hematological parameters (hemoglobin; 80 g/L, MCV; 86fL) without any febrile episodes.

Discussion
Our patient's dramatic response to nutritional supplements in our case supports the notion that the pyrexia was attributable directly to megaloblastic anemia secondary to vitamin B 12 and folate deficiency rather than anything else, as was ruled out by appropriate available diagnostic modalities. As per the modified Petersdorf criteria, 2 FUO is defined as: 1) a temperature exceeding 38.3°C; 2) duration of the fever of more than three weeks; and 3) evaluation of three outpatient visits or three days in hospital. Our patient satisfied two out of the three criteria (1 and 3).
In a study by Tahlan et al. 3 the incidence of low-grade fever in nutritional megaloblastic anemia varied from 28% to 60% (259 of 509 patients). Another study from Northern India described persistent low-grade fever in 70% of the females with B 12 and/or folate deficiency. 4 McKee, 5 reviewed 122 patients of nutritional megaloblastic anemia for the presence of pyrexia (temperature≥37 .8°C [100°F]). In 49/122 (40%), pyrexia was attributable solely to the megaloblastic disease. In addition, the majority of the patients had a minimal rise of temperature (≤38.5°C). Only occasionally the values were above 38.5°C (102°F), and rarely were they greater than 40°C (4/49, 8%). Those with severe disease characterized by high MCV, low hematocrit (<20%), low thrombocytopenia (<100×10 9 /L), high LDH (>1000 IU/L), and unconjugated hyperbilirubinemia (>1.5 mg/dL) were more likely to be febrile. In the majority of the patients, fever subsided 24 to 72 hours after supplementation of vitamin B 12 and/or folate, suggesting the rapid correction of ineffective hematopoiesis.
A comparative review of literature highlighting pyrexia in megaloblastic anemia is presented in table 1. Carpenter et al. 6

described a 38
year old female patient who presented with chronic, low-grade intermittent fever (37.8°C),  MCV: mean corpuscular volume; Hct: hematocrit; TLC: total leukocyte count; TPC: total platelet count; #: gastro-esophageal junction; Hb: hemoglobin; WNL: within normal limit mild macrocytosis (MCV=104 fL), and normal hematocrit secondary to chronic atrophic gastritis, low vitamin B 12 (115 pg/mL, reference range: 190-900 pg/mL), and co-existent proximal intestinal type gastric adenocarcinoma. The pathophysiological mechanism for her pyrexia could have been attributed to either nutritional deficiency secondary to chronic atrophic gastritis of pernicious anemia or release of tumoral cytokines (Interleukin-6); or both. However, response to vitamin B 12 supplementation therapy was not documented in that case, and the patient expired due to metastatic disease following gastrectomy. Negi et al. 7 reported a case of anicteric male with pyrexia (39.7°C), bicytopenia, and macrocytosis (MCV=105 fL) secondary to B 12 deficiency (105 pg/mL). Singanayagam et al. 8 reported a young male with pyrexia of 6 weeks' duration (38.8°C), severe pancytopenia, and mild hyperbilirubinemia secondary to folate deficiency (1.2 ng/mL, reference range: 5-24 ng/mL) and low normal vitamin B 12 (202 pg/ mL). The present report described a case of megaloblastic anemia in a middle-aged female patient, who presented with low-grade pyrexia, pancytopenia, macrocytosis (114.3 fL), very high LDH (10,550 IU/L, reference range: 225-420 IU/L), and mild unconjugated hyperbilirubinemia; secondary to combined deficiency of B 12 (59.6 pg/ mL) and folate (3.9 ng/mL). In all the three cases (including the present one) as was described above, pyrexia subsided 24 to 72 hours after initiation of supplementation therapy. The exact cause of fever in megaloblastic anemia is unknown and at present, seems more hypothetical rather than conclusive. Association of pyrexia and megaloblastic anemia appears to be causal, whereas in other types of anemias, it seems more coincidental. Megaloblastic anemia is a panmyelosis, characterized by hypercellular marrow and ineffective hematopoiesis. Premature destruction of hematopoietic precursors possibly releases intracellular substances, which might function as systemic pyrogens. As was suggested by the researchers, dramatic response to B 12 and/ or folate supplementation (within 24 to 72 hours) strongly supports the above-said hypothesis. Alternatively, the defective oxygenation at the thermoregulatory center of the hypothalamus might be the explanation for pyrexia. However, lack of correlation between neurological manifestation and pyrexia in megaloblastic disease does not support this theory. 5 Moreover, studies have also shown that a rise in temperature might cause depletion of folate stores, both in red blood cells and serum, leading to disturbance of folate metabolism. So whether pyrexia is the cause of folate deficiency or vice versa is yet to be fully understood. 9

Conclusion
All patients presenting with pyrexia and cytopenia should be carefully evaluated for possible vitamin B 12 and folate deficiency in order to prevent the unnecessary use of antibiotics. Larger studies highlighting the possible role of cytokine signaling and bone marrow stromal microenvironment might throw some light in understanding the pathophysiological mechanism of pyrexia in megaloblastic anemia.